WHO inspections of Contract Research Organizations. The prequalification project.
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The prequalification project started in 2001 to assure medicinal products supplied for procurement meet WHO norms and standards (quality, safety, efficacy) (http://mednet3.who.int/prequal/)Requirements for prequalification:1. Quality part of dossier acceptable2. Safety/efficacy part of dossier acceptable3. Manufacturing site (FPP, API) compliant with WHO norms and standards for GMP4. Study compliant with norms and standards for GCP (WHO) and GLP (GPNPCL, and OECD as appropriate)
Contract Research organization (CRO)
A scientific organization (commercial, academic or other) to which a sponsor may transfer some of its tasks and obligations. Any such transfer should be defined in writing.
Good Clinical Practice (GCP)
A standard for clinical studies which encompasses the design, conduct, monitoring, termination, audit, analyses, reporting and documentation of the studies and which ensures that the studies are scientifically and ethically sound and that the clinical properties of the pharmaceutical product (diagnostic, therapeutic or prophylactic) under investigation are properly documented.
Good Laboratory Practice (GLP)*
A quality system concerned with the organisational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported (OECD)
*as applied to human bioanalysis studies
Products to be prequalified usually multisource (generic) products
Therapeutic equivalence generally demonstrated by bioequivalence study in CROs
Findings of deficient and discrepant bioequivalence data and non-compliance with norms and standards for GCP (WHO) and GLP (WHO GPNPCL, and OECD as appropriate)
Guidelines for good clinical practice (GCP) for trials on pharmaceutical products. WHO Technical Report Series, No. 850, Annex 3, 1995.
Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. WHO Technical Report Series, No. 863, 1996.
OECD Principles of good laboratory practice (GLP). [C(97)186/Final], 1997.
Good practices for national pharmaceutical control laboratories. WHO Technical Report Series, No. 902, Annex 3, 2002
CRO inspections performed by WHO May-Nov 2004
Team of 3 inspectors
6 CROs in India (all for HIV/AIDS products)
General organization, the protocol, protection of trial subjects, responsibilities of the investigator, responsibilities of the sponsor/monitor, record-keeping and handling of data, handling and accountability for pharmaceutical products, quality assurance for the conduct of a clinical trial
Apparatuses/materials/reagents, SOPs, performance of the study, test and reference products, storage and retention of records and materials, quality assurance
PK analysis and statistics
Transfer of responsibilities from sponsor to CRO not documented
Unclear procedure for assigning Subject ID (two subjects assigned the same ID on the Attendance Sheet Form!)
No SOP for drug dispensing
No SOP for assigning study numbers
No site staff sample signature log for the study
Organization chart not readily available, no version date
No QC system to ensure accuracy and consistency in recording and document control
Validity of screening tests?
No CRFs designed for the study (raw data not transferred to CRFs)
In some cases, several CRFs missing – only a few still available as archived
Name and address of sponsor
Description of trial site and information on investigators
Method and procedure of randomisation, randomisation schedule and how it was established
Method and timing of subject allocation to investigational groups
Information to volunteers
Procedures for maintaining subject identification code list
Statistical justification for the number of subjects
Method for measuring blood pressure - sitting or supine? And if both, which value to use…
Type of test tubes for blood sampling
PK analysis; Method of calculating PK pararmeters, e.g. AUC, how to deal with deviations from planned sampling times
How to evaluate the results, including statistics and how to handle withdrawals
Independence of EC questionable
Chairman had expanded his own authorisation (Chairman's approval invalid)
Unclear whether study protocol, ICF and related documentation had been properly discussed at the EC meeting
Unclear if one or two ICFs
Unclear when EC convened
Discrepancy between EC approval form and the minutes of the corresponding meeting (who present/who absent)
Some relevant EC documents (register page) could not be produced
Screening before EC approval
No written consent before screening (e.g. lab tests)
Freely given informed consent/valid written consent?
One subject signed ICF with thumb print…
ICF seriously lacking in information
Professional terminology (Stevens-Johnsons syndrome, thrombocytopenia etc)
Identification system (finger print matching) to ensure volunteers had not participated in another study within the last 3 months not validated
No measures to protect confidentiality of subjects
No protocol deviations according to the study report!
However a number of deviations:
Source of reference product unclear (US, UK or India?)
Amount of meal/time for consumption only recorded for some subjects
Deviations in some of the meal times (not mentioned in the study report)
No anticoagulant in tubes contrary to protocol (or different anticoagulant)
ESR and plasma cholesterol required but not done
Na, K, Cl, bleeding time and ECG not required, however tests were done
Protocol and ICF were supposed to be reviewed by EC but ICF appears not to have been
Vital signs recorded at absolute rather than relative timepoints contrary to protocol
Blood sample drawn at times contrary to protocol – deviations not mentioned in the study report
Incomplete recording of vital signs
One subject's identity not verified
Date of birth of subjects?
Violations of incl/excl criteria
No maintenance, calibration or log book for X-ray machine
Investigator CV not signed or dated – CV current?
No monitors appointed by the sponsor. No monitoring/audit reports available.
No evidence of assessment of the trial site (labs, equipment, staff, facilities)
Audits performed by the sponsor, but scheduled after the report was issued and no audits reports available
Issues with certificate of insurance subscribed by the CRO
No study or protocol number on ECGs to link them to the study.
Of 95 ECGs copied by inspectors, 43 appeared to have been recorded from one subject, 21 from a second subject and 11 from a third subject
For several subjects the "screening" and "follow up" ECGs appeared to have been recorded from different subjects
No mention on ECG print outs of the identity of the equipment used
Some ECGs had no date of birth of subject
Doubts as to the authenticity of ECG documentation!
No mention of name, batch no or expiry date of the in vitro diagnostic serology test kit in source doc's or lab data
Discrepancies between Attendance Sheet Forms and CRF Screening pages (screening visit dates)
Discrepancies between Volunteer Card and CRF (smoking/alcohol)
Unclear dosing time
Identical (actual) blood sampling times for two subjects!
Recordings of actual sampling times - same handwriting, however initials of phlebotomists different at different sampling times!
Deviations from planned blood sampling times not reported
Inconsistencies in screening dates
Deliberate attempt to change subject code
Discrepancies between source documents and study report
Method/procedure of randomization not documented
No record of subjects screened
Source documents not kept
Original entry erased!
Type of tubes and anticoagulant used not documented
CRF used was not specific to the study
Errors on the CRFs
Lab ref ranges on CRF different from those reported by the lab
Expiry date of medications not recorded on CRFs
Appearance of tablets incorrectly described
Missing: Lab data, ECG…
Final study report not signed by the monitor
What was given?
How much was given?
Treatment sequence? Cross-over?
Dispensing or dosing? Confusion between the two!
Dispensing not documented. SOP? Dispensing dates?
QA system in place at all (see above)?
No records of labels printed
No record of reconciliation procedure
No SOP for labelling/dispensing of empty vials and return of filled vials
No SOP for further sample handling (centrifugation etc)
No SOP for blood sampling
No SOP for sample transport
No SOP in the event of freezer break down
No SOP for handling of out-of-specification results
No record/minutes of a pre-study meeting
SOPs from before 2001 not archived or available during the inspection
Pipettes not identified – no traceability
Infrequent or no controls of balance (calibrated weights?)
No validation of time of freezer temp recording
Record of freezer contents?
Expiry date for Vacutainers?
Calculation of concentrations
Type of C18 cartridges used (solid phase extraction) not described in the method SOP and not reported in the study report
Only one SOP ("Calculation and reporting of bioanalytical data") for the bioanalytical part of BE trials
SOPs from before 2001 not archived or available during the inspection (most of the ones for the study in question)
Acceptance criteria for analytical runs not in accordance with study plan
Chromatograms without unique study number
Bioanalytical method used =method described in the study report?
No or improper source documents
Errors in documentation re preparation of stock solutions, calibration and control samples
Discrepancies between volumes prepared and volumes actually used
Origin of blank plasma?
Identical chromatograms with different identities
Integration reports of identical chromatograms showed different peak areas, even though peak integration parameters were identical
Identical chromatograms had different peak areas but the same area percent
Inconsistencies noted between visual appearances of peaks and the area in the integration reports
Long term stability of plasma samples?
Authenticity of chromatograms and peak areas?
Interferences at retention time of lamivudine – concentrations still used and reported
Discrepancies between concentrations printed on chromatograms and reported, and those recalculated by the inspectors from the calibration curve parameters
– method failed validation acceptance criteria
Batch numbers of reference substances used not documented – were the batches used, those for which CoAs were available?
Not possible to verify purity of reference substances!
Only uncertified copies of chromatograms at the CRO (original chromatograms reportedly sent to sponsor)
Documents relating to chromatographic analysis of samples not available during the inspection.
The number and critical nature of the deviations from OECD GLP (below) highlight the lack of or insufficiency of the Quality Assurance system implemented by the CRO
Method of calculating AUC not specified in the study report
AUC stated as calculated up to 8 hs when in fact it was up to last conc, 24 hs
PK and statistical calculations
Same or different stock solution for calibration/control samples?
Concentrations <LOQ or LOD reported – SOP not followed
Some zidovudine conc's were lamivudine conc's
Discrepancy between conc on chromatogram and in study report
Composition of buffer for sample preparation not in SOP
Not specified in study protocol/report which results to use
Errors in the bioanalytical report